The insulin-like growth factors (IGF-I and -II) are important determinants of fetal growth and postnatal development. Baker, J., et al. Cell 75, 73–82 (1993); and Stewart, C. E. H., and Rotwein, P. Physiol. Rev. 76, 1005–1026 (1996). IGF bioactivity is modulated by IGF binding proteins (IGFBPs), which, in turn, are regulated by specific proteases. Clemmons, D. R. Cytokine Growth Factor Rev. 8, 45–62 (1977); and Fowlkes, J. L. Trends Endocrinol. Metab. 8, 299–306 (1997).
PAPP-A increases IGF bioavailability and mitogenic effectiveness in vitro through regulated cleavage of IGFBP-4. PAPP-A is a large placental glycoprotein, present in the serum of pregnant women in increasing concentrations throughout pregnancy. PAPP-A in pregnancy serum is linked via a disulfide bond to the proform of eosinophil major basic protein (proMBP), forming an approximately 500 kDa 2:2 complex, denoted PAPP-A/proMBP. The serum form of PAPP-A is derived from a pre-proprotein containing a putative 22-residue signal peptide, a pro-part of 58 residues, and a 1547-residue circulating mature polypeptide. The amino acid sequence shows no global similarity to any known protein, but it contains two sequence motifs common to the metzincins, a superfamily of metalloproteases, three Lin-12/Notch repeats known from the Notch protein superfamily, and five short consensus repeats known from components of the complement system. Free PAPP-A cannot be isolated from pregnancy serum, but can be isolated in conditioned media from human fibroblasts.
The PAPP-A/proMBP complex is absent from maternal serum in pregnancies where the mother is carrying a fetus with Cornelia de Lange syndrome. Recently, PAPP-A and proMBP in conjunction with SP1 have been shown to be effective markers for detecting fetuses affected with Down's syndrome in weeks 7–12 of gestation.